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Inspections of intrastate blood collection establishments in 1974 indicated several widespread problems: slightly less than half the inspections revealed failure to adequately establish donor suitability, about the same percentage demonstrated problems with their blood collection techniques, and half exhibited faulty hepatitis testing. To get a better handle on the massive effort to regulate the blood and blood product industries, the Bureau of Biologics initiated a database, the Blood Establishment Inspection and Registration System—finalized in 1976—to monitor the thousands of annually renewed registrations and licenses, the biennial inspections of several thousand facilities, the compliance history and progress with the firms, and impact of regulatory changes.

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protein fractions had the Hepatitis B Antigen.In 1975, FDA issued a regulation requiring that all blood, plasma, or serum used for biological products must be tested by the latest, “third generation,” technology. This included reverse passive hemoagglutination and radioimmunoassay, which were 10 to 100 times more sensitive than the most common test required since 1972, counterelectrophoresis. Results from FDA’s contractual partner in evaluating the latest testing procedures, the New Jersey Department of Health, indicated that the new testing technologies would identify and thus eliminate from consideration as many as two times as many units of hepatitis-contaminated blood.

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Prompted by concerns with the transmission of the AIDS virus, FDA launched an intensive inspection program of all blood banks and plasma centers in 1988. Over eleven percent of the facilities were found to have significant enough violations to prompt a regulatory response. These problems included the processing of blood suspected of contamination with the AIDS virus, although there were no cases where blood or products confirmed to be so contaminated were released. During this program inspections of American Red Cross (ARC) blood banks in Nashville and Washington, D. C. indicated operational errors leading to the release of unsuitable units of blood and blood products, errors that continued despite corrections. So, in 1988 FDA and ARC signed a voluntary agreement in which the latter would improve operations across the nation by establishing closer oversight of regional operations by national headquarters, standardizing operating procedures, and monitoring more closely computerized information to prevent release of unsuitable blood.

Despite the 1988 voluntary agreement agency inspections of ARC facilities across the nation continued to present compliance failures, followed by formal regulatory notices and initiation of proceedings to revoke establishment licenses. In May 1993 ARC agreed to a consent decree, enforceable by court order, that stipulated a comprehensive series of changes to ensure the safety of the nation’s blood supply and the integrity of ARC’s blood program. Among the changes:  establishing a clear line of managerial control over quality control in all regions;  establishing a comprehensive quality control program;  enhancement of a training program to be required—along with an annual competency review—for all staff engage in blood programs, improvement of its computer system, records management, and its policies for following up on reporting errors, accidents, and adverse events; and annual performance audits of each of its 47 blood program regions.

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Regulation of the biologics marketplace can take many different forms and must be equipped to pivot quickly to address countless threats to public health. For example, Congress appropriated $300,000 for FDA to hire 48 temporary investigators to help prevent the diversion of DBS-cleared lots of licensed Salk polio vaccine from legitimate distribution channels—those used by the six producers to ship vaccine to the states and then to public and private distributors.  FDA provided the training, oversight, and on-site assistance for the temporary staff. Though unclear how long this program would last, the agency did not encounter any missing vaccine.  A case from 2003 illustrated another turn the regulation of biologics could take. FDA’s Office of Criminal Investigations, established only shortly before, announced the discovery of counterfeit Procrit (epoiten alfa) in the marketplace. Some samples were contaminated with bacteria, and FDA laboratories found others completely lacking in active ingredient. Both the manufacturer and FDA alerted healthcare providers and patients as well to the problem and the lot numbers in question. Four months later Criminal Investigations announced three convictions in this case, though it was unclear if patients had been injured by the counterfeit product.counterfeit product.

Office of Therapeutic Research and Reviews

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FDA issued the first license for human leukocyte typing sera in 1975, making it broadly available for use in identifying potential donors for organ transplants and transfusions.  The following year the Bureau established a histocompatibility testing laboratory to provide quality assurance testing and to create reference standards for anti-human leukocyte typing serums proposed for commercial release.  In 1982 the Bureaus of Biologics and the Bureau of Medical Devices agreed, and the FDA Commissioner approved that leukocyte typing sera would be delicensed and regulated as an in vitro diagnostic under the Medical Device Amendments of 1976.

In May 2005 new regulations took effect requiring human tissue firms to properly screen and test donors among other aspects of operations.  These also provided for swift action to be taken by FDA in the interest of public health.  Applying these new regulations early in 2006, FDA issued to a Ft. Lee, New Jersey, human tissue recovery firm an order to immediately cease all manufacturing operations.  The agency monitored the recall of all their tissues to ensure completeness of the operation.  So egregious were the deficiencies in the firm’s manufacturing practices, donor screening, record keeping, and other operations that, according to a senior agency official, “allowing the firm to manufacture would present a danger to public health by increasing the risk of communicable disease transmission.”

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On June 1, 1989, CBER approved epoetin, a treatment for anemia due to chronic kidney failure. This was a copy of erythropoietin, the protein responsible for stimulating reproduction and growth of red blood cells in bone marrow. Blood transfusions were the typical approach to treating severe anemia, though those came with a host of risks and problems. Though this approval was limited in scope, other studies were underway to assess epoetin in several other applications linked to anemia, such as anemia-induced cancer chemotherapy and AIDS.
Botulinum Toxin A, an injectable treatment for eye conditions such as strabismus, was licensed by CBER in 1989.

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Two licenses CBER issued early in 1991 served a critically important need for patients recovering from cancer chemotherapy. Both of these, Sargramostim (rhu GM-CSF) and Filgrastim (rhu G-CSF), were genetically engineered growth factors to help regulate generation of myeloid cells (bone marrow-produced white cells). Sargramostim aided those treated for non-Hodgkin’s lymphoma, Hodgkin’s disease, and acute lymphoblastic leukemia by speeding bone marrow growth that was transplanted as part of the treatment post-chemotherapy.  Accelerating production of white blood cells in this way reduced the amount of time when the patient was most susceptible to infection by a third. Filgrastim decreased infection in chemotherapy patients by regulating the body’s neutrophil production.

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CBER licensed Herceptin (trastuzumab) in September 1998, a monoclonal antibody that represented a new approach to treatment of metastatic breast cancer. Bioengineered from an altered antibody in a mouse, the monoclonal antibody bound to HER2, a protein that regulates cell growth that is found on certain normal cells. This ability to bind to the protein enabled the antibody to interfere with tumor cell growth. In metastatic breast cancer, about 30 percent of the tumors express excess HER2, so this would be useful only in patients with tumors of that character. FDA approved Herceptin alone for those who received little benefit from chemotherapy or as a first-line treatment when used in combination with paclitaxel.
    

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Dive preface class grid-row grid-gap Dive preface class grid-col-6 Image Added Dive preface class grid-col-6 Image Modified Span class caption Dr. Lance A. Liotta, at right, and Dr. Emanuel F. Petricoin, at left. Span class credit FDA History Office

 
The 2007 Food and Drug Administration Amendments Act gave the agency authority to require a manufacturer to submit and carry out a Risk Evaluation Mitigation Strategy (REMS) for selected biologics or drugs to ensure a product’s benefits outweigh its risks as a condition of the product’s approval. FDA issued its first guidance under this authority in 2009. The elements of a REMS included a variety of communication devices to help inform the patient about using the therapy, such as medication guides and patient package inserts; a communication plan for the healthcare provider; and other elements to ensure safe use of the product aimed at the prescriber, dispenser, and the patient. The draft guidance addressed the format and content of the REMS, its assessment, and a timetable for submitting it.

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